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Drug Metabolism / Biotransformation

Dr Kiew LV

Objectives

Define drug elimination and describe the two processes of elimination, i.e.
metabolism and excretion

List the major phase I and phase II reactions and give examples of enzymes (esp.
CYP450 enzymes) involved in metabolism.

Describe the effects of drug metabolism (esp. in liver) and the clinical relevance of
drug metabolism.

General info on
drug metab.

General Rx steps
+ exceptions

MFO & Cyp450


En. Induction /
inhibition

Enzyme info +
Rx examples

Genetics

Drug Elimination

All processes which reduce


the effective drug concentration
in the body fluids

Two main mechanisms:


- Metabolism / biotransformation
(in liver + other tissues)
- Excretion (in kidney & GIT)

Drug biotransformation / metabolism

Conversion of drugs into another chemical species by body enzymes

Purpose:
To inactivate drug (detoxification / remove drugs therapeutic effects)

Location: Mainly in liver cells (smooth endoplasmic reticulum, sER)

General direction for conversion:


inactivate the drug and make the drug more polar / hydrophilic (for renal
excretion) via Phase I & Phase II metabolisms

Drug

Phase I Rx

Inactive** polar
drug metabolite

Phase II Rx

Excreted if the metabolite is sufficiently polar

Very polar inactive drug


metabolite conjugate
Excreted

Drug

Phase I Rx

Inactive** polar
drug metabolite

Phase II Rx

Very polar inactive drug


metabolite conjugate

Excreted if the metabolite is sufficiently polar

Excreted

Phase I Rx: + polar group

excretion

Drug

H
excretion
Water soluble metabolite

OH
Phase II Rx:
+ bigger polar
group (conjugate)

bigger polar
group

Drug

Phase I Rx

Inactive** polar
drug metabolite

Phase II Rx

Excreted if the metabolite is sufficiently polar

Very polar inactive drug


metabolite conjugate
Excreted

** Although phase 1 reaction intends to deactivate drugs, the reaction may also:
converts a pharmacologically inactive compound (a prodrug) to
pharmacologically active drug.
e.g.
levodopa dopamine
enalapril enalaprilat
zidovudine AZT-triphosphate
turn an active drug into active / reactive / toxic metabolites
e.g.
diazepam nordiazepam oxazepam (more active)
paracetamol N-acetyl-p-benzoquinoneimine (NAPQI)
(reactive/toxic)

Drug biotransformation / metabolism


Phase 1
Objective

Phase 2

To add / unmask a polar functional


group to drug (e.g. OH, NH2, SH,
COOH)
serves as the point to attack in
phase II reaction

To add a conjugate to the polar functional groups of the


phase I drug metabolite
phase II metabolites (much more polar & often inactive*)
* except for a few, e.g. morphine 6-glucuronide

Drugs are either inactivated / activated


Location

sER

sER

sER

sER

Cytosol

Cytosol

Cytosol

Main Rx

Oxidation

reduction

hydrolysis

Glucuronidation
(most common)

Sulphation

Acetylation

Glutathione
(GSH)
conjugation

Main
enzymes

Mixedfunction
oxygenase
(MFO)
system

Cytochrome
P450
reductase
(part of MFO)

Esterase &
Amidase

UDPglucuronosyl transferases
(UGT)

Sulfo transferases

N-acetyl transferases

Glutathione
Stransferases

* cytoplasmic alcohol dehydrogenase: oxidize alcohol

Bile acid-CoA
: amino acid
N-acyl
transferases

Oxidation: add oxygen

Alkyl

Glucuronidation: add glucuronic acid

alcohol
Sulphation: add sulphate

Hydrolysis:
breakdown molecule, + water
Ester

Alcohol

Acid

Acetylation: add acetyl group

Reduction: Add hydrogen / remove oxygen


-N=N- or -NO2

azo

nitro

-NH2

amines

Glutathione conjugation: add glutathione (GSH)

e.g. drug metabolism: Paracetamol metabolism


* Around 5% paracetamol will
take this path

P2

P1

P2

N-acetyl-p-benzoquinoneimine
(NAPQI):
- Toxic paracetamol metabolite
- may accumulate in the liver
when GSH is depleted
fulminant liver failure
- GSH will deplete in cases of:
- Paracetamol overdose
- Fasting
- Antidote: acetylcysteine

P2

Microsomal enzymes in the liver

Enzymes of the smooth ER (sER) of liver cells = microsomal enzymes


Reason: when isolated from liver cells for in vitro study, sER reform itself into vesicles
called microsomes

Main microsomal enzymes in the liver :


enzymes of the mixed-function oxygenase (MFO) system

MFO system : 4 components, catalyze drug oxidation

Cytochrome P450
Cytochrome P450 reductase
NADPH as a proton carrier
O2

Drug-H + O2 + 2H+ + 2e Drug-OH + H2O

Other microsomal enzymes:


catalyze reactions e.g. dehydrogenation, hydroxylation, epoxidation, oxygenation

Mixed-function oxygenase (MFO) system

Cytochrome P450
-

key enzymes in MFO system & phase 1


drug metabolism

important enzyme in pharmacogenetics /


pharmacogenomics studies

has many subtypes


Enzymes

Substrates

CYP2E1

Acetaminophen

CYP2D6

dextromethorphan

CYP1A2

Acetaminophen,
caffeine, polycyclic
hydrocarbons

CYP3A4
Acetaminophen,
(most abundant) nifedipine, cyclosporine
CYP2C19

omeprazole

* Acetaminophen = paracetamol

Other locations for drug metabolism


Location

Substrate / drug metabolized

GIT epithelial cells

Tyramine, salbutamol, NA, adrenaline

Lung epithelial cells

Prostaglandin E2

kidney epithelial cells

Imipenam

Skin epithelial cells

Betamethasone , Sulfamethoxazole

Plasma

ACh, suxamethonium, procaine

Enzymes involved:
MFO, monoamine oxidases (MAOs), Catechol-O-methyltransferase (COMT),
peroxidases, plasma cholinesterase etc.

Metabolic enzyme induction vs. drug metabolism


Drugs /substance

Target en.

Effect on enzyme

Influence on other drugs activity

Phenobarbitone

CYP450
(CYP2B1)

Induction
(

warfarin metab. warfarin eect

CYP450
(CYP3A4)

Induction

paracetamol metab.

CYP450

Induction

Phenobarbitone

Phenytoin

(pharmacokinetic drug tolerance)

N-acetylp-benzo-quinone imine (NAPQI)


toxicity

Carbamazepine

benzodiazepines & cyclosporin metab.


benzodiazepines & cyclosporin effect

Rifampicin
Polycyclic
hydrocarbon
(chemicals in
cigarette smoke )
Cabbage

CYP450

Induction

theophylline (bronchodilator) metab.


theophylline effect
(pharmacokinetic drug tolerance)

Metabolic enzyme induction / inhibition vs. drug metabolism


Drugs /
substances

Target
enzyme

Effect on enzyme

Influence on other drugs activity

Cimetidine

CYP450

Inhibition

warfarin metab. warfarin effect

CYP450

Inhibition

benzodiazepines & cyclosporin metab.

Sulphonamides
Ketoconazole
Grapefruit juice
Alcohol
(acute ingestion)

* Chronic ingestion of
alcohol induces CYP450

benzodiazepines & cyclosporin effect

Genetic predisposition & drug metabolism

Differences in genetic (inherited) makeup among


individuals affect drug metabolism.

Pharmacogenetics :
The study on the genetic differences that cause the variation in patient drug response

Variations in genetic makups of individual


code different drug metabolizing enzyme subtypes that has different level of
activeness

Slow metabolizer: people with enzyme that process (metabolize) drugs slowly
Accumulation of drug risk of toxicity

Fast metabolizer: people with enzyme that process (metabolize) drugs quickly
Fast elimination of drug risk of underdose
Pharmacogenomics : Study on the influence of genetic variation on drug response in patients by
correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity.

Genetic predisposition affecting pharmacokinetics


Enzyme

People

e.g. drug

effect

Nacetyltransferase

slow acetylators

Isoniazid
(treat tuberculosis)

Higher [plasma isoniazid],


longer t1/2 in slow acetylators

Plasma
pseudocholinesterase

Low level enzyme

Suxamethonium

Prolonged muscle relaxation


in individual with low level
enzyme (> 3hr vs. 6 min in
normal)

fast acetylators

Normal level enzyme

cannot breathe on their


own as soon after surgery
need a ventilator for an
extended time.
Cytochrome P450
enzyme (CYP2D6)

Metabolizer type:

Ultra-rapid
Extensive / fast
Intermediate
Poor

Codeine
(changed into
morphine by
enzyme)

Variable analgesic effects